Substituted 3-(5-nitro-2-furyl)-pyrazoles

ABSTRACT

Compounds of the class of 5-amino-4-carbamoyl-3-(5-nitro-2furyl)-pyrazole substituted in 1-position of the pyrazole ring by alkyl or hydroxyalkyl have anti-microbial properties; these compounds are active ingredients of pharmaceutical and feedstuff compositions; they are useful for the treatment of microbial infections and for protecting organic material against microbial attack; a typical embodiment is 5-amino-4-carbamoyl-1-methyl-3(5-nitro-2-furyl)-pyrazole.

United States Patent Howarth et al.

[15] 3,682,956 1 Aug. 8, 1972 [54] SUBSTITUTED 3-(5-NlTRO-2-FURYL)- PYRAZOLES [72] Inventors: Graham Arton I-Iowarth, 13 Hope Ave., Wi1mslow;-William Hoyle, 61 Valley Rd., Bramhall, both of England [22] Filed: June 4, 1970 [21] Appl. No.: 43,585

[52] US. Cl ..260/3l0 R, 260/347.7, 424/273 [51] Int. Cl. ..C07d 49/36 [58] Field of Search ..260/31O R [56] References Cited UNITED STATES PATENTS 3,487,083 12/1969 Cresswell et a1. ..260/31O R FOREIGN PATENTS OR APPLICATIONS 42/108 l/l967 Japan ..260/31OR 42/23,427 11/1967 Japan ..260/310R OTHER PUBLICATIONS Haber et al. Chem. Abst. Vol. 70, No. 68242f 1969) Ponomareu et a1. Chem. Abst. Vol. 71, N0. 3040lq (1969) Sasaki et al. Chem. Abst. Vol. 69, No. 96563j (1968) Primary Examiner-Natalie Trousof Attorney-Karl F. Jorda and Bruce M. Collins [57] ABSTRACT Compounds of the class of 5-amino-4-carbamoyl-3-(5- nitro-2-fury1)-pyrazo1e substituted in l-position of the pyrazole ring by alkyl or hydroxyalkyl have antimicrobial properties; these compounds are active ingredients of pharmaceutical and feedstufi compositions; they are useful for the treatment of microbial infections and for protecting organic material against microbial attack; a typical embodiment is 5-amino-4- carbamoyl-l-methyl-3-(5-nitro-2-furyl)-pyrazole.

6 Claims, No Drawings SUBSTITUTED 3-(5-NITRO-2-FURYL)- PYRAZOLES DETAILED DESCRIPTION The present invention relates to substituted 5-amino- 4-carhamoyl-3-(5-nitro-2-furyl)-pyrazoles with antimicrobial activity. It further relates to pharmaceutical and feedstuff compositions as well as to methods for the treatment of microbial infections of mammals and to methods of protecting organic material against microbial attack.

More particularly, the present invention pertains to compounds of formula wherein p R is alkyl having at most five carbon atoms or hydroxyalkyl having from two to five carbon atoms. If R is alkyl, then it may be a straightor branchedchain alkyl group. Preferably it will contain from one to three carbon atoms. Examples of alkyl groups are I: CO-NH? HN LNH R (IA) and any specified compound of the present invention may occur in either these tautomeric forms or as a mixture of both of them. In this specification, however, the compounds of the present invention are regarded for purposes of clarity as having the formula I and are thus described and exemplified vas being S-nitrofurylpyrazole derivatives.

Compounds of the present invention are produced according to a first process comprising hydrolyzing a nitrofuryl-pyrazole derivative having formula II,

(abut J CN ll wherein R is as previously defined.

The process may be carried out under conventional hydrolytic conditions, preferably those conventionally used in the acidic hydrolysis of nitriles, for instance by treating with aqueous sulphuric acid withina temperature range of between 0 and I00C. Preferably the hydrolysis is effected at a reaction temperature of between and C. Preferably, the compound of. formula II is heated with a mixture of concentrated sulphuric acid and ethanol during a reaction time of from 1 to 2 hours, and at a temperature of from 90 to 100 C. The resulting reaction product may then advantageously be poured into an excess of water to precipitate the desired S-nitrofuryl-pyrazole of formula I.

The starting compounds of formula II may be prepared by reacting the corresponding S-nitrofurylnitrilimine, which in one of its mesomeric forms may be represented by the formula III,

R (III) with malononitrile.

The nitro-furyl-nitrilimine of formula III may conveniently be generated, during the course of the reaction with malononitrile, by treating the corresponding nitrofuryl-a-halo-hydrazone having the formula IV,

(IV) wherein X is halogen, and

R is as defined before with a base. The process may,

if desired, be effected in the presence of a further conventional hydrogen halide acceptor. The halogen present in the halohydrazone of formula IV is preferably chlorine or bromine.

The nitrofuryl-a-halo-hydrazones of formula IV are new compounds. They may be produced, for example, by reacting the corresponding nitrofuryl-hydrazones having the formula V,

(V) with an N-halo compound bearing the requisite halogen. Examples of N-halo compounds which may be used, are N-halo benzotriazoles and N-halo succinimides. Of the N-halo succinimides, the N-chloro compound may be used, but the N-bromo derivative is? preferred.

According to a second process a compound falling under formula I, and having formula I,

one-[ O NIl-:

wherein R' is alkyl containing at most five carbon atoms, is

prepared by hydrolyzing and deacylating a compound of formula VI,

wherein R is alkyl and R is as defined before by treating it with a protonating agent in a polar solvent, and then hydrolyzing the protonated intermediate. According to a third process, a compound falling under formula I, and having formula I",

wherein R" is hydroxyalkyl having from two to five carbon atoms, are prepared by hydrolyzing and deacylating a compound having formula VI],

(VII) wherein R is lower acyl, and A is alkylene having from two to five carbon atoms, by treating it with a protonating agent in a polar solvent and then hydrolyzing the protonated intermediate.

In the hydrolyzing and deacylating'processes, the preferred protonating reagent is ethanolic hydrogen chloride, 40 percent w/w being a suitable concentration. Other protonating agents, such as sulphuric acid in other polar solvents, may also be used.

The second and third processes according to the invention are essentially similar. The only difference is that in the second process the substituent R as alkyl group is unchanged, whereas in the third process the substituent AOR is itself deacylated to form a hydroxy alkyl group. v

Normally both the second and third processes according to the invention will involve heating the starting material with a protonating agent such as ethanolic hydrogen chloride for a period of time sufficient to ensure, reaction, then cooling the reaction mixture-and either adding ice/water, or pouring the reaction mixture into ice/water to precipitate the desired product. The processes are carried out at temperatures between C. and the boiling point of the polar solvent.

The starting materials of formula VI used for the second process according to the invention, may be prepared by acylating a compound of formula ll,

wherein R is alkyl having at most five carbon atoms with an acylating agent containing the acyl group R OzNI CN N NH2 wherein R" is hydroxy alkyl having from two to five carbon atoms, in order to introduce the acyl group R2.

. These compounds of formula ll" may be prepared by a similar series of reactions as described above, starting from a suitably substituted nitrofuryl nitrilimine.

The compounds of the present invention of formula I and formula Vll have valuable anti-microbial properties, in particular have anti-bacterial, anthelminthic, anti-protozoal coccidiostatic, trypanocidal and antimalarial activity of value in human or veterinary medicine. The compounds are particularly valuable in the treatment of infections of the intestinal and urinary tracts. The compounds may also be used to protect a high molecular weight hydrophobic or other organic material susceptible to bacterial or other microbial deterioration by contacting the organic material with,

impregnating in, or otherwise treating with, the compounds. The compounds also find application as growth-promoting additives to animal feedstuffs.

The anti-microbial properties of the compounds of the invention are demonstrated in a variety of standard in vitro and in vivo tests. Thus, 5-amino-4-carbamoyl-l -methyl-3-(5-nitro-2-furyl)-pyrazole and 5-amino-4- carbamoyl-l -(2-hydroxyethyl )-3-(5-nitro-2-furyl pyrazole have been found to have an excellent activity against Staphylococcus, Escherichia coli, Klebsiella, Salmonella and other bacteria.

The toxity of the compounds of the invention as determined in mice on oral administration is of favorably low order.

For their internal use in mammals, the compounds of formula I are administered orally in daily dosages of from about i to about 50 mg/kg, although the exact dosage has to be adjusted to the type of infection, the age, weight and the particular condition of the host being treated.

The compounds of the present invention are administered advantageously in form of a pharmaceutical composition comprising an anti-microbially effective amount of a compound of formula I and a pharmaceutically acceptable carrier therefor.

The pharmaceutical compositions according to the invention contain at least one compound of formula I a For external application, for example in disinfecting healthy skin, disinfecting wounds and in treating dermatoses and infections of the mucous membranes caused by bacteria, ointments, powders and tinctures are particularly useful. The ointment bases may be anhydrous, for instance they can consist of mixtures of wool fat and soft paraffin, or they can consist of aque-' ous emulsions in which the active substance is suspended. Suitable carriers for powders are for instance, rice starch and other starches; the bulk weight of the carriers may be made lighter, if desired, for example by adding highly dispersed silicic acid, or may be made heavier by adding talcum. The tinctures may contain at least one active ingredient of formula I in aqueous ethanol, in particular 45 to 75 percent ethanol, to which to percent of glycerol may be added, if desired. Solutions prepared from polyethylene glycol and other conventional solubility promoters, and also optionally, from emulsifying agents, may be used with particular advantage in disinfecting healthy skin. The content of active ingredient in pharmaceutical compositions for external application is preferably in the range of from 0.1 to 5 percent.

Gargles or concentrates for their preparation, and tablets for slow dissolution in the mouth, are suitable for the disinfection of the mouth and throat. The former are preferably prepared from alcoholic solutions containing 1 to 5 percent of active substance to which glycerol or flavorings may be added. Lozenges, that is solid dosage units, preferably have a relatively high content of sugar or similar substances and a relatively low content of active substance, for instance 0.2 to 20 percent by weight, as well as the usual conventional additives, such as binding agents and flavorings.

Solid dosage units, in particular tablets, dragees (sugar coated tablets) and capsules, are convenient for use in intestinal disinfection and for the oral treatment of urinary tract infections. These units preferably contain from 10 to 90 percent of the compound of formula I, to enable the administration of daily dosages of from 0.1 to 2.5 grams to adults, or of suitably reduced doses to children. Tablets and dragee cores are produced by combining the compounds of formula I with solid, pulverulent carriers such as lactose, saccharose, sorbitol, maize starch, potato starch or amylopectin, cellulose derivatives or gelatines, preferably with the addition of lubricants such as magnesium or calcium stearate or polyethylene glycols of suitable molecular weight. Dragee cores may then be coated, for example with concentrated sugar solutions which can also contain gum arabic, talcum and/or titanium dioxide, or they may be coated with a lacquer dissolved in volatile organic solvents or a mixture of solvents. Dyestuffs can be added to these coatings, for instance to differentiate between varying dosages. Soft gelatine capsules consist, for example, of a mixture of gelatines and glycerol and may contain, for example, mixtures of the compound of formula I with polyethylene glycol. Hard gelatine capsules contain, for example, granulates of an active substance with solid pulverulent carriers, for instance lactose, saccharose, sorbitol, mannitol, starches (such as potato starch, maize starch or amylopectin),

cellulose derivatives of gelatines, and magnesium stearate or stearic acid.

In all forms of administration, compounds of the formula I can be present as sole active ingredients or they can also be combined with other known pharmacologically active, and especially anti-bacterial and/or antimycotically or other anti-microbially active substances, for example to broaden the range of applications. They can be combined, for example, with 5,7-dichloro-2- methyl-8-quinolinol or other derivatives of 8-quinolinol, with sulfamerazine or sulfafurazole or other derivatives of sulfanilamide, with chloramphenicol or tetracycline or other antibiotics, with 3,4,5- tribromosalicylanilide or other halogenated salicylanilides, with halogenated carbanilides, with halogenated benzoxazoles or benzoxazolones, with polychlorohydroxy-diphenylmethanes, with halogen-dihydroxydiphenyl sulphides, with 4,4 '-dichloro-2-hydroxydiphenylether or 2,4,4'-trichloro-2-hydroxydiphenylether or other polyhalogenhydroxydiphenylethers, or with bactericidal quaternary compounds or with certain dithiocarbamic acid derivatives such as tetramethylthiuram disulphide. Also, carriers which themselves have favorable pharmacological properties may be used, for instance sulphur, as a powder base or zinc stearate as a component of ointment bases.

The invention also provides a method of protecting an organic material susceptible to bacterial or other microbial attach which comprises treating the material with a compound of formula I. The organic material may be, for instance, a natural or synthetic polymeric material, a proteinaceous or carbohydrate substance, or a natural or synthetic fiber or textile material formed therefrom.

The invention also provides ananimal feedstuff composition comprising a compound of formula I, in an amount sufficient to promote the growth of the animal fed with the composition.

The following examples will serve to further typify the nature of the present invention, but they, in no'way, should be construed as a limitation on the scope thereof. The temperatures are given in degree Centigrades.

EXAMPLE I a. To a prepared mixture of 40 ml of concentrated sulphuric acid and 40 ml of ethanol are added 20 g of 5- amin o-4-cyanol -methyl-3 5-nitro-2-furyl )-pyrazole and the resultant mixture is stirred on a steam bath at to C. for 90 minutes. The reaction mixture is then diluted with 500 ml of water and stirring is continued until crystallization is complete. The crude product was collected, washed with water and recrystallized from water.

The product is 5-amino-4-carbamoyl-l-methyl-3-(5- nitro-2-furyl)-pyrazole, having melting point 242 C. with decomposition;

b. The starting material 5-amino-4-cyano-l-methyl- 3-(5-nitro-2-furyl)-pyrazole is prepared as follows:

To a stirred solution of l6.9 g of 5-nitro2-furaldehyde N'-methylhydrazone dissolved in I00 ml of dimethylformamide is slowly added 17.8 g of N- bromosuccinimide at 20-30 C. After further stirring, the mixture is cooled to 10 C.

To the stirred mixture is then added 6.6 g of malononitrile followed by the slow addition of a mixture of NH g of triethylamino and 25 ml of dimethyllormamidc at l20C.

After further stirring, the mixture is diluted with 500 ml of iced water and the precipitate is collected, washed with water and dried. The dried solid is recrystallized from ethyl acetate.

The product is -amino-4-cyano-l-methyl-3-(5- nitro-2-furyl)-pyrazole having melting point 250 C. with decomposition; ln an analogous manner are prepared:

c. 5-Amino-4-cyanol -isopropyl-3-( 5-nitro-2-furyl )-pyrazole;

5-Amino-4-cyanol -(n-pentyl )-3-( 5nitro-2-furyl)-pyrazole; e. 5-Amino-4-cyano-l-(2-hydroxyethyl)-3'-(5-nitro- 2-furyl)-pyrazole, M.P. 216 C; f. 5-Amino-4-cyanol -ethyl-3-( S-nitro-2-furyl pyrazole, MP. 189 C;

g. 5-Amino-4-cyano-l-n-propyl-3-(5-nitro-2-furyl)- pyrazole, M.P. 165C.

EXAMPLE 2 The procedure described in Example la is carried out using 5-amino-4-cyano-l -isopropyl-3-(5-nitro 2-furyl)-pyrazole as starting material instead of 5-amino-4- cyano-l-methyl-3-(5-nitro-2-furyl)-pyrazole, the reaction conditions being the same.

The product is 5-amino-4-carbamoyl-l-isopropyl-2- (S-nitro-Z-furyl)-pyrazole.

EXAMPLE 3 The procedure described in Example la is carried out using 5-amino-4-cyano-l-(n-pentyl)-3-(5-nitro-2- furyl)-pyrazole as starting material instead of S-amino- 4-cyanol -methyl-3-(5-nitro-2-furyl )-pyrazole, the reaction conditions being the same.

The product is 5-amino-4-carbamoyl-l-(n-pentyl)-3- (5-nitrot2-furyl)pyrazole.

EXAMPLE 4 The procedure described in Example la is carried out using 5-amino-4-cyanol 2-hydroxyethyl )-3-( 5- nitro-2-furyl)-pyrazole as starting material instead of 5- amino-4-cyan0-l-methyl-3-(5-nitro-2-furyl)-pyrazole, the reaction conditions being the same.

The product is 5-amino-4-carbamoyl-l-(2-hydroxyethyl)-3-(5-nitro-2-furyl)-pyrazole, having melting point 202 C.

EXAMPLE 5 a. A mixture of g of 5amino-4-cyano-1-( 2- hydroxyethyl)-3-(5-nitro-2-furyl)-pyrazole and 200 ml of acetic anhydride is heated under reflux for 4.5 hours and then evaporated to dryness under reduced pressure. The solid residue on recrystallization from aqueous dimethylformamide gives S-acetamido-l-(Z- acetoxyethyl)-4-cyano-3-(5-nitro-2-furyl)-pyrazole, M.P. 191 C.

b. A mixture of 12.0 g of 5-acetamido-l(2-acetoxyethyl)-4-cyano-3-(5-nitro-2furyl)-pyrazole and 50 ml of ethanolic hydrogen chloride (40 percent w/w) is heated under reflux for minutes and cooled.

To the mixture is then added lOO ml oficc/water and the precipitated solid is collected. recrystallized from water and dried. The product is 5-amino-4-carbamoyll-(2-hydroxyethyl)-3-(5-nitro-2-furyl)-pyrazole having melting point 202 C.

EXAMPLE 6 To a solution of 23.3 g of 5-amino-4-cyano-l-methyl- 3-(5-nitro-2-furyl)-pyrazole dissolved in a mixture of ml dimethylformamide and 70 ml pyridine is added 7.8 g of acetyl chloride and the mixture is heated under reflux for 2 hours. After cooling, the mixture is diluted with ml of ice/water and 5-acetamido-4-cyano-lmethyl-3-(5-nitro-2-furyl)-pyrazole which is precipitated, collected, washed with water and dried, M.P. 250 C.

The procedure described in Example 5 is repeated using the 5-acetamido-4-cyano-l-methyl-3-(5-nitro-2- furyl)-pyrazole as the starting material instead of 5- acetamidol 2-acetoxyethyl )'4-cyano-3-( 5-nitro-2- furyl)-pyrazole, the reaction conditions being the same.

The product is 5-amino-4-carbamoyl-l-methyl-3-(5- nitro-2-furyl)-pyrazole, having melting point 245C.

EXAMPLE 7 5 -Acetamido-4-cyano-3-(5-nitro-2-furyl)-1-(npropyl)-pyrazole (M.P. 215C.) is prepared in a similar manner to 5-acetamido-4-cyano-l-methyl-3-(5-nitro-2 -furyl)-pyrazole described in Exampleb, starting from 5-amino-4-cyano-3-( 5-nitro-2furyl )-l -(n-propyl pyrazole.

The procedure described in Example 5 is carried out using the 5-acetamido-4 cyano-3-(5-nitro-2-furyl)-l- (n-propyl)-pyrazole as starting material instead of 5- acetamidol 2-acetoxyethyl )-4-cyano-3-( 5 -nitro-2- furyl)-pyrazole, the reaction conditions being the same.

The product is 5-amino-4-carbamoyl-3-(5-nitro-2- furyl)- l -(n-propyl)-pyrazole, having melting point 198 C.

EXAMPLE 8 5-Acetamido-4-cyanol -ethyl-3-( 5-nitro-2-furyl pyrazole is prepared in a similar manner to 5- acetamido-4-cyanol -methyl-3-(5-nitro-2-furyl pyrazole described in Example 6, starting from 5- amino-4-cyanol -ethyl-3-( 5-nitro-2-furyl )-pyrazole.

The procedure described in Example 5 is carried out using 5-acetamido-4-cyanol -ethyl-3-( 5-nitro-2-furyl pyrazole as starting material instead of S-acetamido-l- (2-acetoxyethyl )-4-cyano-3 5-nitro-2-furyl )-pyrazole the reaction conditions being the same.

The product is 5-amino-4-carbamoyl-l-ethyl-3-(5- nitro-2-furyl)-pyrazole, having melting point 210 C.

EXAMPLE 9 The procedure described in Example 1 is carried out using 5-amino-4-cyanol -ethyl-3 S-nitro-2-furyl pyrazole as starting material instead of 5-amino-4- cyano-l-methyl-3-(5-nitro-2-furyl)-pyrazole, the reaction conditions being the same.

The product is 5-amino-4-carbamoyl-l-ethyl-3-i(5- nitro-2-furyl)-pyrazole, having melting point 210 C.

EXAMPLE 10 The procedure described in Example 1 is carried out EXAMPLE 1 1 Preparation of Tablets A mixture consisting of 100 g of -amino-4-carbamoyl-l-methyl-3-(5-nitro-2-furyl)-pyrazole, 60.0 g of maize starch and 35.0 g of lactose is moistened with a solution of 5.0 g of gelatin and 3.0 g of glycerol in 70.0 g of water and granulated through a sieve. The granulate is mixed with a mixture of 15.0 g of talcum, 10.0 g of maize starch and 2.0 g of magnesium stearate. The resulting mixture is pressed into 1.000 tablets, each containing 100 mg of active substance. If desired, the tablets can be grooved for better adaption of the dosage.

EXAMPLE 12 Preparation of Dragees Composition for 1.000 dragees: l S-Amino-4carbamoyl-1- (2-hydroxyethyl)-3-(S- Composition 1 is granulated in the heat with composition 11 through a sieve of 1.2 mm mesh diameter. The dried granulate is mixed with composition Ill and the resulting mixture is pressed into 1.000 dragee cores. These are then coated with composition 1V and dried. The dragees obtained weigh 255.0 mg and contain 100 mg of active substance.

EXAMPLE 13 Preparation of a Syrup Composition: 5-Amino-4-carbamoyll 2-hyd roxycthyl 3-(5-nitro-2-furyl)-pyrazole 100.0 g Colloidal silicon dioxide l3.0 g p-Hydroxybenzoic acid methyl ester [.4 g p-hydroxyhenzoic acid propyl ester 0.6 g Citric acid 1.0 g Sodium cyclamatc 5.0 g Distilled water M00 g Glycerol 100.0 g Sodium carboxymethyl cellulose 40 g Sugar 320.0 g

Total: 1,155.0 g

The active substance and the colloidal silicon dioxide are passed through a sieve of 1.2 mm diameter (1).

The p-hydroxybenzoic acid esters, the citric and the sodium cyclamate are dissolved in the given amount of boiling distilled water; the glycerol is then added to this solution (11). The sodium carboxymethyl cellulose and the sugar are thoroughly mixed (Ill).

Composition III is then added at C. to solution [I under stirring until complete dissolution of Ill. The viscous, slightly turbid liquid is cooled to room temperature, filtered, if necessary, and mixed with composition Water is added to the resulting mixture up to the prescribed weight of 1.1550 g, and the syrup obtained is homogenized.

What is claimed is:

l. A compound of the formula 1,

CONHz g I UNITED s ATEs PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3,682, 956 Dated August 8, 1972 I v fl GRAHAM ARTON HOWARTH et al I it is certified that efror appears in the above-identifiedpatent and that said Letters Patent are hereby corrected as shown below: 7

Column 1, insert Assignee: CIBA-GEIGY Corporation, Ardsl'ey, New York Signed and, sealed this 9th day of April 197R;

(SEAL) Attest: v EDWARD MTFLETCHERJR. c. MARSHALL DANE Attesting Officer Commissioner of Patents aaa 

2. A compound according to claim 1, wherein R is hydroxyalkyl of two or three carbon atoms.
 3. A compound according to claim 1, wherein R is methyl.
 4. A compound according to claim 1, wherein R is ethyl.
 5. A compound according to claim 1, wherein R is propyl.
 6. A compound according to claim 1, wherein R is 2-hydroxyethyl. 